A rare human variant that disrupts GPR10 signalling causes weight gain in mice

• Published in: Nature communications Vol. 14; no. 1; p. 1450
• Main Authors: Talbot, Fleur, Feetham, Claire H., Mokrosiński, Jacek, Lawler, Katherine, Keogh, Julia M., Henning, Elana, Mendes de Oliveira, Edson, Ayinampudi, Vikram, Saeed, Sadia, Bonnefond, Amélie, Arslan, Mohammed, Yeo, Giles S. H., Froguel, Philippe, Bechtold, David A., Adamson, Antony, Humphreys, Neil, Barroso, Inês, Luckman, Simon M., Farooqi, I. Sadaf
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.03.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 631/208/2489; 692/163/2743; 96/109; Animals; Body mass index; Body weight gain; Body weight loss; Brain; Diabetes; Energy balance; Energy expenditure; Energy Metabolism; Food intake; Homeostasis; Hospitals; Humanities and Social Sciences; Humans; Life Sciences; Ligands; Metabolism; Mice; Mice, Transgenic; multidisciplinary; Obesity; Obesity - genetics; Proteins; Receptors; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Science; Science (multidisciplinary); Signal Transduction; Signaling; Therapeutic targets; Transgenic mice; Weight Gain - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36966-3

Disruption of brain-expressed G protein-coupled receptor-10 (GPR10) causes obesity in animals. Here, we identify multiple rare variants in GPR10 in people with severe obesity and in normal weight controls. These variants impair ligand binding and G protein-dependent signalling in cells. Transgenic mice harbouring a loss of function GPR10 variant found in an individual with obesity, gain excessive weight due to decreased energy expenditure rather than increased food intake. This evidence supports a role for GPR10 in human energy homeostasis. Therapeutic targeting of GPR10 may represent an effective weight-loss strategy. The brain-expressed receptor GPR10 is involved in energy homeostasis in mice. Here the authors identify rare loss of function variants in GPR10 in people with severe obesity and showed that one of these variants causes obesity when modelled in mice, suggesting that future studies could explore GPR10 as a potential target for weight-loss therapy.